Impressions from the January 2019 Juvenescence Gathering

The JP Morgan Healthcare conference took place in San Francisco this past week. The conference is less interesting in and of itself, but it is the spur for any number of other short gatherings of various biotech investment and business interest groups. So in the middle of last week, Jim Mellon and the other Juvenescence principals were in town to host their second annual showcase for startups working on aging, and the BioAge and Felicis Ventures folk hosted the overlapping Extending Human Lifespan event on the same day. I had to miss that second one, as I was presenting Repair Biotechnologies at the Juvenescence event to a small crowd of other entrepreneurs, angel investors, and venture capitalists of varied allegiances, and stayed for the whole event to see the other presentations.

Many of our fellow travelers associated with SENS rejuvenation research and Methuselah Foundation spheres were present to meet and greet: the SENS Research Foundation folk; much of the Oisin Biotechnologies team; Doug Ethell of Leucadia Therapeutics; Frank Schüler of Forever Healthy Foundation; a number of angel investors I've interacted with in the past while we were interested in the same companies; and many others arriving and leaving as they moved between events.

One thing that caught my eye is that the theme of diversity and new hypotheses in Alzheimer's research (or outright rebellion against the past two decades of relentless focus on clearing amyloid via immunotherapies, present it as you will) has robustly made its way to the commercial development stage. Leucadia Therapeutics were presenting their latest work on ferrets as an animal model to illustrate that the development of Alzheimer's occurs due to blocked drainage of cerebrospinal fluid though the cribriform plate. Related company Enclear Therapies was not present, but was a topic of discussion given that their founders have very similar thoughts on filtration of cerebrospinal fluid. Maxwell Biosciences principals presented their work on the LL-37 antimicrobial peptide as a test of the microbial theories of Alzheimer's disease, in which infection is provoking greater aggregation of amyloid and inflammation to accelerate other aspects of the condition. An attempt at intervention is perhaps the best way to clear up questions of causality here: do we see microbial infections in the Alzheimer's brain because they are an important cause, or because immune dysfunction in general tends to be more advanced in these patients?

A further contingent of startups at the Juvenescence event were similarly of interest for having a good shot at answering scientific questions very much faster than the academic community can, due to the influx of resources from the venture community. Elevian falls into this category, with their work on GDF11. Early work on parabiosis, joining the circulatory systems of an old and young mouse, pointed to GDF11 as a possible factor in conveying benefits to the old mouse. There is now some debate over why parabiosis works, however, casting doubt on the argument of beneficial factors in young blood. Similarly, there has been some back and forth in the research community regarding whether or not past work on GDF11 is as it appears to be, but the Elevian staff claim to have resolved the conflicts. In many cases, the best way to resolve a debate of this nature is to just forge ahead and try to build a therapy; that effort can pull in much greater funding more rapidly than the academic community can manage via the usual channels available to researchers.

Another item that caught my attention, and seems worthy of consideration, is that the infrastructure and drug discovery companies in our space of treating aging as a medical condition are the furthest ahead in terms of building out relationships with venture concerns, obtaining larger funding, and breaking ground on their larger and later projects. This may reflect the focus of groups like Juvenescence from the past couple of years, their approach to establish an initial presence in a field. Examples of this trend include In Silico Medicine and Ichor Therapeutics' portfolio company Antoxerene, both of which offer faster, cheaper discovery of small molecule drugs for any sort of use, but both of which happen to have founders very interested in aging and longevity over and above any of the myriad other uses for their technologies. In Silico Medicine in particular is clearly advancing by leaps and bounds in Asia as they gather support from the high-end venture groups there.

(I'll confess that I've never found the development of lower level biotechnological infrastructure all that interesting as a topic. Obviously it is vital, and acceleration of technological progress is achieved by making common tasks easier, faster, and cheaper. Someone has to do it, invest in it, and focus on it, but that someone will never be me. I am far more interested in specific implementations of rejuvenation therapies, the development groups who might end up using the infrastructure to build a given treatment).

San Francisco is ever a hub of connections for the venture and technology spaces. It is the base of operations and home for a sizable number of high net worth individuals, agents for other high net worth individuals, fund partners deploying sizable amounts of capital, successful founders turned angel investors, successful angel investors turned founders - all rubbing shoulders, bumping into one another at the supermarket, and two degrees of separation removed at most. It is through this very connected network that interest in the biotechnologies of rejuvenation has been spreading these past fifteen years, pushed along by the presence of the SENS Research Foundation in the Bay Area. This occurred slowly at first, given that the focus was initially philanthropic funding of research rather than startups, but much more rapidly these past few years now that the first rejuvenation biotechnology startups are arriving on the scene.

At a small gathering after the Juvenescence event, those attending included an older AI-focused entrepreneur-turned-investor who has a growing interest in biotechnology, and a recently successful young founder from the technology space who is now taking life science classes to get up to speed on what he considers to be his next area of interest. The next day I met with an angel investor who attended the Juvenescence event, and who is cheerfully incorporating biotech companies into his previously tech-company-heavy portfolio. This dynamic is similarly reflected in venture firms such as Y Combinator, Felicis Ventures, and (closer to our community) Kizoo Technology Ventures led by Michael Greve, among others. They are transitioning into biotechnology, and the interest in doing something about aging is a driving motivation for many involved. For others, it is the realization that successful rejuvenation therapies will lead to a market so enormous as to make a pittance of near everything that has come before. Self-interest is a machine to be harnessed in these matters: while fundamental research is very cheap, later commercialization and distribution of medical therapies to millions of patients is enormously expensive. We need the deep pockets to enter this space, and to pull in all of their allies and other interested parties, if we are to see a reasonable rate of progress in moving rejuvenation therapies from lab to clinic.

The only other alternative is some form of major, lasting revolution in the regulatory environment, as that is the dominant cause of cost and delay. Therapies could be brought to market just as safely as they are today at a fraction of the present cost; the majority of cost and time imposed by the FDA, EMA, and the like is entirely unnecessary, some of it the debris of regulatory capture used by larger pharmaceutical entities to suppress competition, some of it the consequences of bureaucrats going to any lengths to avoid negative press, even by the means of preventing most new technologies from ever being approved. I'm certainly in favor of great upheaval in the development of medical therapies, but tearing down the present edifice is a vast project, and arguably one that will be much less costly and difficult to undertake given the existence of the first rejuvenation therapies and the public demand for more.

A final thought on investors and the science of rejuvenation: most of the newcomers are still finding their way to an understanding of the science in this space. They cannot yet tell the difference between projects likely to produce significant gains in human life span, those based on repair of the damage that causes aging, and those that cannot in principle produce large gains, those based on, say, upregulation of stress responses, such as mTOR inhibitors. Investors are guided by potential for financial gains, but that metric is not in fact a great way to tell the difference between better and worse approaches to aging. The typical competently run medical biotechnology company is acquired or goes public before the final determination of effectiveness of their programs; perhaps somewhere just after the first human trial, or even prior to that when the market is hot. Companies can do this after showing marginal benefits, or even just potential for marginal benefits, with a therapy that will never produce large or reliable benefits in larger patient populations, and yet still realize large gains for the early investors. So this is a challenge, and an opportunity for patient advocates to make a difference - to help guide those people chasing gains into obtaining those gains by backing better rather than worse technologies.

Comments

Regulation: to what degree does regulation look like an obstacle because at present there are no effective therapies? If those existed, even based on first or second phase trials, wouldn't medical tourism quickly burst the regulatory dam, so to speak?

Posted by: Jamie_NYC at January 14th, 2019 3:20 PM

An interesting review, but some devil's advocate thoughts to avoid complacency

I maintain the main thing that really matters in the short term for the entire industry is the success of the Unity UBX0101 study in OA

If it succeeds, it will engender much more interest in the space

If it fails, or yields modest results (like the recent D&Q Kirkland study) it could bring on a bit of an investor winter

Unity is the only company in the space (with maybe the exception of ResTORbio) that has legitimate institutional biotech investors behind it to support it for the longer run - while it doesn't have a big pharma partner yet, success with the trial could bring such a partnership in reach

But it has what Wall Street wants - an easy to understand drug entity, in humans, in a large therapeutic market segment

Most everything else is a bit less important in the present scheme of things

- Jim Mellon / Juvenescence has lost much credibility in placing the majority of his $$ bets on AgeX - slapping Aubrey DG's face on a NewCo next to perpetual disappointer Mike West, while they issue pr pumping press releases about mice studies or the next conference they will appear at, is going to go nowhere - the street is fed up with the last 30 years of failed promises - It was actually BioTime corporate that made out big by getting lots of cash and West out as CEO

- No "anti-aging drug discovery shop" is going anywhere - this model has never worked and never will - companies raise $10-20 million from investors selling the old "we can make your drug discovery more effective" story, they do a few deals for early stage discovery services with big pharma, and then things dry up waiting for some type of royalty stream to materialize - which it never does due to the odds - so investors end up gutting the company as they try and turn it into a traditional drug development shop

- Medical tourism is a niche and will always remain one - this business is about millions of patients using your product - not about a small group of enlightened bio-hackers sneaking off to Colombia to let "geniuses" like those at BioViva experiment on you for a million $$ - that will not support the future

- The newbie funds are trying to do admirable things but they do not have the band width of more established life science VCs to really lead rounds and dictate direction - until they do, they will have to continue to take positions of being follow on investors in larger syndicates and hoping for some decent liquidity event "hits" down the road

- Regulation is usually more of a problem on the back end - it is relatively easy to get FDA approval to study therapeutics - it is another thing to have therapeutics approved - the crazier the intervention, the harder the process becomes at the agency - so there is a big difference between George Church being allowed to study 45 gene therapies as one "product", and FDA ever approving such a product

Posted by: David Permisov at January 15th, 2019 8:17 AM

@David Permisov
So what do you think are the chances of success in having a working human therapy by George Church in the next 5-6 years ?

Posted by: cuberat at January 15th, 2019 9:28 AM

@cuberat

Close to 0% in the traditional world of things

Current FDA guidance for gene therapy INDs has very little to say about combination products, other than their vague statement about the "regulatory status of the components"

https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610795.pdf

It is questionable about what this means, but for the most part they are draconian with regard to combos

Posted by: David Permisov at January 15th, 2019 10:46 AM

@David Permisov
and what are the chances of those therapies working in human, provided the FDA approval wasn't an issue?

Posted by: cuberat at January 15th, 2019 12:35 PM

@David Permisov, how about the prospects for overseas approval in such places like Japan that has fast tracked approval for stem cells? Perhaps these companies could start making real money overseas first while waiting out the FDA. That would hopefully be enough to keep them going and word would get out that really effective medicine is only available elsewhere than the U.S. Then Americans might demand access.

Posted by: Morpheus at January 15th, 2019 1:46 PM

@cuberat

I am not a gene therapy expert by any degree

George Church is clearly a thought leader and knows what he is doing per the core science - so from that angle you probably would want to listen to him - but what happens at the level of humans (and then obviously at the level of the regulators) is anyone's guess

@Morpheus

Yes - you are right

The question is will there ever be enough momentum from the medical tourism space to support the bigger picture?

The typical mantra is that the foreign data will be good supporting evidence for the program at "home" and decent $$ will have rolled in abroad to support real comprehensive development

I just don't know if this is the case yet in the medical tourism feild

Posted by: David Permisov at January 15th, 2019 2:50 PM

I really hope at next years conference Jim mellon announces a 30 million investment in repair therapeutics.

Posted by: Jimofoz at January 15th, 2019 8:33 PM

@space_cowboy

As it is an increased dose cohort, I think it highlights good tolerability so far

If they were going lower, I'd be worried

Posted by: David Permisov at January 16th, 2019 7:27 AM

@David Permisov agree with you on the relevance of the Unity Study to the potential success/setback of the nascent longevity industry, would be happier to see at least 3 different companies in the space with studies of similar importance, singe point of failure is never a good position.
What do you think on the approach of and strategy behind the TAME trial?
Looks like your bet is really on the established life science VCs, can you imagine any alternative routes to success?
Cheers, Attila

Posted by: Attila Csordas at January 17th, 2019 7:46 AM

@Attila Csordas

TAME is interesting for the data that will flow from it, but I'm not holding my breath for meaningful lifespan gains

I wish there were realistic alternative routes, but I don't see it for the big late stage funding requirements

And FYI, we just lost two other "deep pockets" this week that need to go on the longevity wall of shame

https://www.washingtonpost.com/business/businessman-and-philanthropist-raymond-perelman-dies-at-101/2019/01/15/80e8ed5c-1911-11e9-b8e6-567190c2fd08_story.html?utm_term=.30e254f97b9d

https://www.forbes.com/sites/baldwin/2019/01/16/jack-bogle-is-gone-but-hes-still-saving-investors-100-billion-a-year/#7cbb44aa795c

Posted by: David Permisov at January 17th, 2019 5:18 PM

@David Permisov

in terms of deep pockets lost, here's what John Arnold, 44yo Texan, now a full-time philantropist, net worth of 3.3 billion USD, thinks of longevity, a thread between him an me on Twitter:
https://twitter.com/JohnArnoldFndtn/status/1054093800203726848

Posted by: Attila Csordas at January 18th, 2019 8:08 AM

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